This application addresses broad Challenge Area (06): Enabling Technologies and specific Challenge Topic, 06-NS-103: Breakthrough technologies for neuroscience. The goal of this project is to develop a strategy to examine the role of specific cell types in the function of cortical circuits. As a proof of principle we have chosen to focus on GABAergic neurons since they can regulate depolarization of postsynaptic excitatory neurons with great spatial and temporal precision, and are likely to play a critical role in regulating the output of cortical activity. We propose to engineer mice in which the activity of GABAergic subpopulations can be acutely and reversibly blocked so that we can assess their contribution to the function of cortical circuits. The proposed technology would be generally useful to the neuroscience community since similar approaches could be used to silence different neuronal populations to study their function in vivo. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a strategy to examine the role of specific cell types in the function of cortical circuits. As a proof of principle we have chosen to focus on GABAergic neurons since they can regulate depolarization of postsynaptic excitatory neurons with great spatial and temporal precision, and are likely to play a critical role in regulating the output of cortical activity. We propose to engineer mice in which the activity of GABAergic subpopulations can be acutely and reversibly blocked so that we can assess their contribution to the function of cortical circuits.